Literature DB >> 28442253

Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology.

Bruce J Melancon1, Michael R Wood2, Meredith J Noetzel1, Kellie D Nance3, Eileen M Engelberg3, Changho Han3, Atin Lamsal3, Sichen Chang3, Hyekyung P Cho1, Frank W Byers3, Michael Bubser3, Carrie K Jones4, Colleen M Niswender4, Michael W Wood5, Darren W Engers1, Dedong Wu6, Nicholas J Brandon5, Mark E Duggan5, P Jeffrey Conn4, Thomas M Bridges7, Craig W Lindsley8.   

Abstract

This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.
Copyright © 2017 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(4); Muscarinic acetylcholine receptor; Non-human primate (NHP); Positive allosteric modulator (PAM); Structure-Activity Relationship (SAR)

Mesh：

Substances：

Year:  2017        PMID： 28442253      PMCID： PMC5508548          DOI： 10.1016/j.bmcl.2017.04.043

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  19 in total

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2.  Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4).

Authors:  Emery Smith; Peter Chase; Colleen M Niswender; Thomas J Utley; Douglas J Sheffler; Meredith J Noetzel; Atin Lamsal; Michael R Wood; P Jeffrey Conn; Craig W Lindsley; Franck Madoux; Mary Acosta; Louis Scampavia; Timothy Spicer; Peter Hodder
Journal:  J Biomol Screen       Date:  2015-04-15

3.  An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.

Authors:  Jana K Shirey; Zixiu Xiang; Darren Orton; Ashley E Brady; Kari A Johnson; Richard Williams; Jennifer E Ayala; Alice L Rodriguez; Jürgen Wess; David Weaver; Colleen M Niswender; P Jeffrey Conn
Journal:  Nat Chem Biol       Date:  2007-12-02       Impact factor: 15.040

4.  Allosteric antipsychotics: m4 muscarinic potentiators as novel treatments for schizophrenia.

Authors:  Martilias Farrell; Bryan L Roth
Journal:  Neuropsychopharmacology       Date:  2010-03       Impact factor: 7.853

5.  Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor.

Authors:  James M Salovich; Paige N Vinson; Douglas J Sheffler; Atin Lamsal; Thomas J Utley; Anna L Blobaum; Thomas M Bridges; Uyen Le; Carrie K Jones; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley; Corey R Hopkins
Journal:  Bioorg Med Chem Lett       Date:  2012-06-06       Impact factor: 2.823

6.  Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

Authors:  Nellie E Byun; Michael Grannan; Michael Bubser; Robert L Barry; Analisa Thompson; John Rosanelli; Raajaram Gowrishankar; Nathaniel D Kelm; Stephen Damon; Thomas M Bridges; Bruce J Melancon; James C Tarr; John T Brogan; Malcolm J Avison; Ariel Y Deutch; Jürgen Wess; Michael R Wood; Craig W Lindsley; John C Gore; P Jeffrey Conn; Carrie K Jones
Journal:  Neuropsychopharmacology       Date:  2014-01-20       Impact factor: 7.853

7.  Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

Authors:  Michael R Wood; Meredith J Noetzel; James C Tarr; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Jarrett J Foster; Emery Smith; Peter Chase; Peter S Hodder; Darren W Engers; Colleen M Niswender; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-07-21       Impact factor: 2.823

8.  Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.

Authors:  Michael R Wood; Meredith J Noetzel; Michael S Poslusney; Bruce J Melancon; James C Tarr; Atin Lamsal; Sichen Chang; Vincent B Luscombe; Rebecca L Weiner; Hyekyung P Cho; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-11-30       Impact factor: 2.823

9.  Synthesis and structure-activity relationships of allosteric potentiators of the m(4) muscarinic acetylcholine receptor.

Authors:  J Phillip Kennedy; Thomas M Bridges; Patrick R Gentry; John T Brogan; Alexander S Kane; Carrie K Jones; Ashley E Brady; Jana K Shirey; P Jeffrey Conn; Craig W Lindsley
Journal:  ChemMedChem       Date:  2009-10       Impact factor: 3.466

10.  Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

Authors:  Michael R Wood; Meredith J Noetzel; Julie L Engers; Katrina A Bollinger; Bruce J Melancon; James C Tarr; Changho Han; Mary West; Alison R Gregro; Atin Lamsal; Sichen Chang; Sonia Ajmera; Emery Smith; Peter Chase; Peter S Hodder; Michael Bubser; Carrie K Jones; Corey R Hopkins; Kyle A Emmitte; Colleen M Niswender; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-05-05       Impact factor: 2.823
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  7 in total

1.  Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands.

Authors:  Michael S Poslusney; James M Salovich; Michael R Wood; Bruce J Melancon; Katrina A Bollinger; Vincent B Luscombe; Alice L Rodriguez; Darren W Engers; Thomas M Bridges; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2018-12-18       Impact factor: 2.823

2.  Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target.

Authors:  Rocco G Gogliotti; Nicole M Fisher; Branden J Stansley; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn; Colleen M Niswender
Journal:  J Pharmacol Exp Ther       Date:  2018-03-09       Impact factor: 4.030

3.  Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping.

Authors:  Madeline F Long; Julie L Engers; Sichen Chang; Xiaoyan Zhan; Rebecca L Weiner; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Darren W Engers; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-10-09       Impact factor: 2.823

4.  SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.

Authors:  Trevor C Chopko; Changho Han; Alison R Gregro; Darren W Engers; Andrew S Felts; Mike S Poslusney; Katrina A Bollinger; Ryan D Morrison; Michael Bubser; Atin Lamsal; Vincent B Luscombe; Hyekyung P Cho; Nathalie C Schnetz-Boutaud; Alice L Rodriguez; Sichen Chang; J Scott Daniels; Donald F Stec; Colleen M Niswender; Carrie K Jones; Michael R Wood; Michael W Wood; Mark E Duggan; Nicholas J Brandon; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley; Bruce J Melancon
Journal:  Bioorg Med Chem Lett       Date:  2019-06-20       Impact factor: 2.823

5.  Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2.

Authors:  Madeline F Long; Rory A Capstick; Paul K Spearing; Julie L Engers; Alison R Gregro; Sean R Bollinger; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Craig W Lindsley; Darren W Engers; Kayla J Temple
Journal:  Bioorg Med Chem Lett       Date:  2021-10-26       Impact factor: 2.823

6.  Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

Authors:  Blake R Bewley; Paul K Spearing; Rebecca L Weiner; Vincent B Luscombe; Xiaoyan Zhan; Sichen Chang; Hyekyung P Cho; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Thomas M Bridges; Darren W Engers; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-08-20       Impact factor: 2.823

Review 7.  Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders.

Authors:  Sean P Moran; James Maksymetz; P Jeffrey Conn
Journal:  Trends Pharmacol Sci       Date:  2019-11-08       Impact factor: 14.819
  7 in total

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